Cancer is one of the most important medical and health problems in the world. As the leading cause of death worldwide, there were 12.4 million new cancer cases and 7.6 million cancer related deaths in 20081. It has been predicted that the deaths from cancer worldwide will continuously rise and 12 million deaths would be caused by cancer in the year of 20301. Breast cancer (BC) is the most common cancer and the leading cause of cancer-related mortality among women2, with 1.38 million new cases and 458,000 deaths in 20083. Although therapeutic advances have improved, most BC patients still suffer from greatly reduced quality of life or even metastasis due to delayed diagnosis2, 4. Although recent genome-wide association studies (GWAS) have successfully detected several genetic variants associated with the risk of BC, no valuable marker for the early detection of BC has been identified. As an early event in the development of cancer, the onset of metastasis in particular in a primary breast cancer patient or the progression-free survival (PFS) or overall survival (OS) of a patient with metastatic breast cancer seems to be a particularly promising tool.
Breast cancer (BC) and specifically metastatic breast cancer (MBC) are major health issues worldwide as they account for the highest number of cancer-related deaths among women1. Early detection of metastasis has been shown to improve the survival rate among BC patients2, while better stratification of patients into good and poor-prognosis groups would lead to a more personalized medicine approach. Although research was conducted on biomarkers for these purposes, the identified markers were confined to specific types of MBC and lacked sensitivity and specificity3-5. Therefore, there is an urgent need for predictive or prognostic biomarkers that can improve the quality of life for these patients. Circulating tumor cells (CTC) have emerged as promising prognostic biomarker in MBC, in general, and has been approved by the FDA, although limitations regarding its enrichment and detection methods are debated6. However, currently, the prognosis and risk assessment is largely achieved by clinco-pathological features such as age of diagnosis, tumor size, number and types of sites of metastasis, receptor status, distant disease-free survival (DDFS), etc.7-9. Nevertheless, there are no markers for early detection of metastasis which could indicate disease spread before being clinically discernible through imaging techniques. Thus, there exists a lacuna in the area of biomarkers for predicting prognosis across all types of MBC and early detection of metastasis in BC. Since their discovery in placenta, circulating miRNAs, which represent the miRNA population in cell-free portion of blood and body fluids, have attracted tremendous interest in the field of biomarker discovery10. Features such as high stability, access by minimally-invasive methods and possibility of repeated sampling make them ideal candidates for use as biomarkers11. As described before, for several types of cancer, in particular BC non-invasive techniques for the early detection are still missing. In addition, it would be highly desirable to have means for determining the susceptibility and risk evaluation for a subject to develop those cancers and to provide a non-invasive, highly efficient, easy, reliable, and low cost method for the early detection of BC, as well as other cancers.
This technical problem has been solved by the embodiments as characterized in the claims and described further below and illustrated in the Examples showing for the first time the identification of circulating miRNAs that can discriminate patients depending on their CTC status and that could predict prognosis in MBC patients by adopting a global profiling approach, followed by validation in two independent cohorts.